Version July 2025
ALGORITHM —
INITIAL EVALUATION —
Total hemolytic complement (measured as CH50 or sometimes as CH100) is a useful screening tool for detecting a deficiency of one or more of the nine components (C1 to C9) of the classical pathway (figure 1). A deficiency may result from either an inherited defect of a single component or from activation of a pathway, leading to lowered levels of several components. The presence of reasonable levels of all nine components is required to give a normal result.
The evaluation for complement abnormalities typically begins with measurement of the antigenic levels of C4 and C3 and a functional assay for CH50. (See "Overview and clinical assessment of the complement system", section on 'CH50'.)
A low CH50 may be due to any of the following (listed from most to least common):
●Laboratory error due to improper specimen handling, especially if C3 and C4 are normal. As this is quite common, CH50 should be measured on a separately obtained sample, to which specific care is given in handling. Serum samples should be assayed within one to two hours on the same day of collection or immediately frozen for subsequent analysis.
●Activation of the classical pathway with immune complex formation (eg, systemic lupus erythematosus [SLE]), reflecting complement consumption (CH50 typically low but detectable, >10 units/mL).
●Laboratory artifact due to what is often referred to as "cold activation," which can occur in the presence of complement-activating immune complexes. Contrary to the common name given, this includes immune complexes that do not precipitate in the cold. It may occur in patients with an inflammatory disease (eg, SLE or chronic viral hepatitis); CH50 is typically very low, ≤10 units/mL or 0.
●Impaired hepatic synthesis of complement proteins due to severe liver disease.
●Genetic deficiency of one or more complement proteins in the classical pathway (CH50 typically very low, ≤10 units/mL or 0) (figure 1).
Review C4, C3 and repeat CH50 — The steps in the evaluation of low CH50 include the following:
●Review C4, C3 antigenic levels (usually available at the time of the initial assessment):
•C4 and C3 levels will be normal but lack functional activity, resulting in falsely low, very low, or undetectable CH50, if the specimen was handled improperly.
•C4 and/or C3 levels will be low in patients with certain systemic autoimmune disorders, especially SLE. Other diseases featuring autoantibodies leading to immune complex formation are the antiphospholipid syndrome (APS), mixed cryoglobulinemia, Sjögren's disease, and membranoproliferative glomerulonephritis.
•C4 may be low (with normal C3 levels) in an individual who inherits a low copy number of C4 genes. (C4 is encoded by two chromosome loci: C4A and C4B. Approximately 1 to 2 percent of the White population lacks both copies of C4A and may have C4 serum concentrations as low as half the usual normal range.)
•C4 and/or C3 will be moderately reduced or normal (with a very low or zero CH50) due to laboratory artifact caused by "cold activation" in the presence of cryoglobulins or other immune complexes.
●Repeat CH50 on a separately obtained sample, especially if the CH50 is very low (eg, ≤10 units/mL), with strict compliance to specimen handling requirements.
If the repeat CH50 is normal or elevated, further evaluation for a complement disorder is rarely required. Many complement proteins can increase in the context of an inflammatory state. Therefore, the detection of an elevated CH50 should prompt evaluation for the cause of inflammation. (See "Acute phase reactants", section on 'Laboratory evaluation'.)
CH50 confirmed low but detectable activity — If confirmed CH50 is low but detectable (eg, approximately >10 units/mL), the patient most likely has activation of the classical complement pathway by autoantibody-mediated diseases (eg, SLE, APS, complement-mediated hemolytic uremic syndrome [HUS], immunoglobulin A [IgA] vasculitis, subacute bacterial endocarditis). (See "Acquired disorders of the complement system".)
Further evaluate as appropriate for the suspected diagnosis.
CH50 confirmed very low or undetectable activity — If confirmed CH50 is very low or undetectable, genetic deficiency of one or more complement proteins in the classical pathway is possible, although this is rare.
Inherited disorders of complement components present predominantly with recurrent bacterial infections and/or SLE. Occasionally, patients with SLE may also have very low CH50 associated with low C4, C3 antigenic levels due to immune complex activation of the classical pathway. (See "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis".)
If a suspected rare genetic deficiency of a complement protein in the classical pathway, obtain:
●C2 antigenic level if not previously measured
●Consider specialty consultation (eg, immunology, rheumatology, genetics) to assist in further evaluation and management
C2 deficiency is the most common genetic cause of a complete deficiency. When possible, the proband (affected family member) should be tested initially to determine the defect and relatives subsequently tested for the identified defect. Other rare causes may be identified by obtaining a sequencing gene panel or whole exome sequence. (See "Inherited disorders of the complement system", section on 'Classical pathway deficiencies'.)
REFERENCE RANGE —
All nine complement components (C1 to C9) are required for a normal CH50. A normal CH50 value/titer ranges from 150 to 250 units/mL in a commonly employed functional assay system. Interpretation of a specific abnormal result should be based upon the reference range reported with that result.
CITATIONS —
The supporting references for this content are accessible in the linked topics.
